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"And the big news, the news that people have spent a lot of time talking about and analyzing and questioning up on is Tysabri. You all know that we filed in the U.S. and Europe on the one-year data. The two year trials continued. One of them is finished. And that data will be available at the AAN in April – that’s the monotherapy trial, and the combination therapy after that. … Biogen has two of the blockbusters in biotechnology in Rituxan and Avonex and we certainly believe along with our partners Elan do as well the Tysabri will fairly shortly show up on this list as well. That’s certainly the object of our research looking for innovative therapies that are going to into .. that we can apply to large unmet needs.
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I will return to the MS franchise. Clearly, we have been a leader in that for some years and with Tysabri, this just solidifies the position and continues to expand it. Tysabri is the only major new advancement in therapy in quite some number of years. So it’s a new mechanism of action and really, a different efficacy profile than we’ve seen with current products on the market. So, we’re going to have what we believe are going to be the #1 and #2 products on the market.

Avonex will #1 for a while but we believe that Tysabri will, in a fairly short period of time, move to the #1 position in the U.S. market and then shortly after that in the other markets around the world. Having said that, Avonex, I think exceeded everybody’s expectations. Last year it continues to be the cornerstone of MS treatment. It is the most convenient self-injectable and it’s got proven long-term efficacy. I think importantly, as Tysabri is launched, this is really the only product that has proven efficacy with Tysabri. The early indicators from a lot of the surveys we’ve seen done by the investment communities would say that the combination therapy is a bit higher than what we had anticipated going into the market.

[Jim Mullen is throughout commenting on various slides available with the presentation.] So this is just the sales progression. At the bottom are the U.S. sales, the gold part on the top are the expanding European or rest of the world sales. The bulk of that is European sales. And you can see a nice re-acceleration after 2002, and the growth rate. And particularly impressive, I think, is how competitive we’ve been outside the U.S., growing the market and taking share back in a lot of the important markets. I think that bodes well for what we can do with Tysabri in these marketplaces. And that brings me to the next segment here.

So here is our goal, out of the box. I think we have been pretty clear about this: we intend to establish Tysabri as the #1 MS product worldwide. In order to do that we first have got to achieve that first-line status in the minds of the physicians and patients. I have to say: the early reception has been very strong. The only thing we need to do to promote this is to go out there with the label at this stage. And I think that most physicians are very impressed with the data.

The second, and this is really going to be the story, I think, for the first 6 months of the launch, is to overcome these barriers to treatment. The access to infusion: we don’t really view infusion capacity to be an issue, but just making sure, the logistics of lining up the patients, the physicians, to get people into the right infusion centers and, of course, the reimbursement. And that means working with each payer, payer by payer by payer, getting their policies in place, going from a manual system to some more routine business. And it’s not only each payer, but it’s each payer plan that goes along with that. So, those just have to be knocked off one at a time. We already see that we are making good progress on there. The reception has generally been very good from the payers. They understand the need to pay for this product, given its efficacy profile. And so, it’s just a matter really of knocking down the hurdles there. Where we hope to be at year end is to have really gotten the logistics behind us, of access to reimbursement, access to infusion, and into more routine business, as well as to work through, if you will, the pent-up demand that was clearly out there prior to the launch, and then have some significant momentum in the U.S. and, of course, hopefully launch in Europe as we leave the year.

I think that many of you are familiar with the product and the profile. It is a novel mechanism of action. I think very importantly in this marketplace, if you look down the side effects, it has a very favorable tolerability profile and none of the flu-like symptoms that are associated with the interferons. And of course, this once every four weeks IV infusion is going to be very powerful. We think that is both a convenience factor as well as something as a compliance issue, factor for patients over time. Certainly, we know that patients get tired if they have to give themselves even the injection once every week, which is the best that it gets, with Avonex. And it’s as bad as once a day.

This is an analyst survey that was done with neurologists by one of the Street analysts. And this is really trying to find out how aware are the neurologists of this product and what is coming and what its profile is, and what is most important to them in the profile. And you can see that it pretty well stacks up with: “reduction in relapse rate”, “less frequent dosing” “reduction in gadolineum-enhanced lesions.” And as you’ll see, I’m going to go to that next, the label that we received from the FDA lines up extremely well with this. Just a comment for those of you who haven’t really followed this market, there are about 17,000 neurologists in the U.S. About 6000 of those drive 90% of the business and we have that very well covered. We increased our sales force from about 90 to roughly double that going into the launch. And so, we think we’ve got excellent coverage.

And this is the label summary as well as just a snapshot of the data, the one-year data from the two Phase III trials. So we got a very broad indication statement with really no limitations from the FDA, so “for patients with relapsing forms of MS to reduce frequency of clinical relapse.” Anybody with active MS has clinical relapse. And, as long as they have been diagnosed with the relapsing form, they fit in the label, which is a very broad label.

We ran two Phase III trials, two quite very large Phase III trials. They ran for two years. One of them is just finishing up; the other one has finished up. This is the one-year data cut, by agreement with the FDA and the EMEA. And on the AFFIRM, it was a monotherapy trial. You see the 66% reduction in relapse rate. That’s a big step up over the current therapies. I think that there are many trials that you can go back and look at across these different products and companies that all return the same result. And I think very importantly, this 96% of the patients were free of gadolineum-enhanced lesions. That is probably the statistic, at least for me, that grabs my attention the most to tell you how powerful this product is in the setting.

The SENTINEL trial, and I’ll caution people, “don’t compare these left to right directly, because the entry criteria in the SENTINEL trial was different.” We had naïve patients in the AFFIRM, and in the SENTINEL trial you had patients who were on Avonex for at least a year and still had evidence of disease activity. And you can see with the addition of Avonex, there was a large incremental benefit that accrued to those patients.

Safety: quite well tolerated. I’m not going to read down through this, because there’s not a lot here that is really at this stage warrants a lot of discussion. One of the things that people just wonder about with infused biologics is, of course, the infusion-related reactions. We did so those fairly typical, relatively mild. Nothing terribly serious that we have been very concerned about there: the usual chills, hives. With the occasional person: discontinue the infusion or treat with some Benadryl, and mostly it’s easier to handle.

One of the surprises to us, of course, was the low rate of immunogenicity, and we have a pretty big data now set on this. And the important part is really differentiating: “What are the persistent antibodies?” 6% of the patients have persistent antibodies. They come on fairly early. We see most of them within the first twelve weeks, as you can see on there. And we do know that if you have a persistent antibody, that does have an impact, ultimately, on the efficacy of the product.

So let me look at the marketplace and just try to build up for everyone how we are viewing the market. There are 30,000–40,000 newly diagnosed patients annually. I’m talking Western Europe and North America. And that’s the vast majority of the market. We estimate that there is about 100,000 patients that have been on one of the four currently approved therapies and have discontinued those at this point in time, roughly evenly divided between the U.S. and Europe. We also believe that there are about 150,000 patients – so if you just go down to these next two bars and you add those together, you have about 350,000 patients that are currently on one of the therapies. 150,000 of those are what we call “treated – relapsing.” So, they’re on one of the treatments, but there is continued evidence of disease activity. And then the last group, “treatment stable”: so those are patients that are currently on one of the therapies and by MRI or clinical relapse, those clinical measurements, they’re basically stable disease or considered in remission. Those patients we would not consider as candidates for Tysabri at this point in time until they have actually fallen into one of the other categories.

So we see, you know, over time, that Tysabri will become the first-line therapy, I think, with the tolerability profile, the highest efficacy in this group and the once-every-four-weeks infusion. We think that’s going to be the logical choice as patients present for the first time. That will take some time, I think, for us go from being early adopters to really being in the center cut of the market. But we fully expect that to happen Our discussions with the neurologists would confirm that. And I think that most of the surveys out there confirm that as well.

Off treatment "quitters": this really is the only new option for those folks. So the challenge is to get those folks back in the neurologist’s office, so they can consider a new treatment. I don’t think we are seeing a lot of those folks yet, because what we are working with is really the next group which is the “treatment – relapsing”. These are the patients who have been going to the neurologist’s office. And in the neurologist’s office, they are going: “What am I going to do to help these folks?” And I think that is the bolus of the people that we have seen, if you will, with the pent-up demand, along with a small number of the newly-diagnosed. We’re starting to attract some of the off-treatment folk back into the marketplace.

So, in short, we are going to drive and try to get Tysabri as the #1 product, the product of choice in those three market segments. And just to make the point, the “treatment stable” isn't, if you will, a stable market segment because, you know, many of the people that are in that grouping now, we think, ultimately, will have some kind of clinical relapse.

So, just to hit on a few things that we have done in the six months. As you know we didn’t really …we had a hope but not an expectation that we would be able to file on the one-year data. Indeed, that data was very strong. We did file. We got a priority approval, a priority review and an approval. And so we had to very quickly accelerate our launch preparations. We hired 450 people in less than 6 months. We were able to use our great sales force out there and go out and profile 1600 of these physician practices in great detail. And we really want to understand how they think about the product. And importantly, how they were going to deal with infusion and how also all the payer issues that were likely to come at them.

We managed to validate over 1800 infusion sites. And well over 1000 of those were ready to administer product at the time of launch. What we have seen is a lot of physicians adding infusion capacity. And I have even seen some examples of hospitals, which really surprised me, adding infusion capacity for Tysabri in advance of approval.

We had a lot of conversations with managed care. Obviously, that has accelerated since launch by some multiples. And we are having good discussions with folks. But that will take time to go through discussions to really having formal policies in place. And we were very quick, as we normally like to be, in getting the product into the marketplace. When you work on one for 15 years, you don’t like to wait a lot of weeks to get the product into the hands of the patients.

Just a few metrics. We have a big call center where as some of you know we handle a lot of the issues for MS patients I think it is one of the differentials in our marketing model. That volume jumped dramatically starting with the announcement of the day of the launch and it has continued. So we are receiving well over 1600 calls a day from patients, well over 50% of those are related to Tysabri.

Those are everything from, you know, questions about MS, questions about products, questions about insurance. We do a lot of the insurance, the pre-insurance verification, pre-prescription insurance verification as part of our services. And we have seen a very broad reception among neurologists. So remember, 6000 represent 90% of the MS scripts. 2000–3000 patients have already made it all the way through the reimbursement and the insurance, the infusion logistics and have been infused. So that now we are talking about an end of the pipe metric. A month ago at the health care conferences, I only talked about the leading indicators, the 2000–3000 are patients that have been dosed. And we have seen over 2000 physicians that have prescribed.

A few more milestones, just to remind everybody, two-year data for both the Phase III trials are due this half of 2005. The AFFIRM trial will be presented at the AAN and we will announce top-line results ahead of that.
Crohn’s disease: we will have Phase III results over the summer.
RA: we will have Phase II results over the summer. We expect the MS approval later in the year. The Crohn’s submission was accepted for filing. That could happen late in the year, more likely early 2006.

Manufacturing: it’s a question a lot of folks have focused on and started to ask product, can you supply it? We have two large scale facilities in place. One is licensed. This is the facility in North Carolina, RTP. The second one is finished, the one in the middle, which is in Oceanside, California. The third one is in Denmark. Just to put a scale around that: that will probably put us at #2 or #3 worldwide in capacity for mammalian cell culture products. Got a lot of questions on this subject on the call on Monday with the investors. And instead of going through lots of detail on just where we are with inventory capacity, what I would say is, if the trajectory of this launch is headed to 40,000 patients or less this year – which would be an extraordinary number, if we got to 40,000 patients – we think we are in good shape to handle that. If it starts to go north of that, there may be some, you know, temporary supply pinch points to the line. But as we expand out these facilities and add on to the license, we think we can stay ahead of that curve, unless we are really just blowing it out.

So, to sum up, you know, the first six months of this is about these last two bullet points: overcoming barriers to treatment, and then start to look towards building momentum in a more normal business routine way as we go out of the year, and hopefully also launching in Europe."
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"Question: I have a question about reimbursement in combination therapy. And you warned us not to compare the AFFIRM and SENTINEL trials side-by-side because you had different patient groups and you defined the differences there. But I’m wondering whether the payers might say to you: “Well, we have nothing else, but this data. And as we look at it side-by-side, the improvement of combination therapy over monotherapy, Tysabri alone, is only a few basis points. And until you can show us a study that compares ‘apples to apples’, this is all we have.” And so the question I have is: do you anticipate or are you experiencing any pushback or resistance in the payer community based on those perceptions?

Jim Mullen: All right. Well, it’s a good question. Of course, it’s our job when we are out there talking to the managed markets, the managed payers in the managed markets, to actually make that case strongly. Because as you point out, that’s the case that can be made on the other side. We’re not currently seeing a lot of push-back by the payers to pay, first, or on combination.
But, personally, and this is what I said on Monday, I’m cautious on that, because I don’t think that the payers right now can match up what’s happening on the combination side. Because most people are getting scripts on the current therapies for 3 or 6 months. And the scripts coming through for Tysabri are all being handled manually, some of them as a medical benefit and not a pharmacy benefit. So, I don’t think that the payers have really started to wrestle with this issue or have seen it yet. They have started to talk about it a little bit. I think part of this is going to be dependant on how strong is the two-year data on disability, on the disability endpoint from the SENTINEL trial. I don’t think it will be that difficult if we get that in front of the payers to get them to understand the difference between the patient populations.
And I think that the conversation so far with the payers are, you know are somewhere of .. you know, on monotherapy there’s no doubt that they need to reimburse that. On combination, they don’t like it, but they probably will pay for it. But I’d say, let’s see what the two-year data says, because that will coincide with about the time when they can actually see combination usage.

Q. My question is on the off-treatment group for Tysabri. How many of those people are seen by neurologists as opposed to the primary care physician? And how flexible are your plans in terms of reaching that group? So, do you think that if you see a very strong ramp in Tysabri this year, maybe you can sort of scale back trying to reach those people, to the extent that if the scripts take off much more slowly, you can speed up that effort?

Jim Mullen: Well, that’s an excellent question. How many of them are still seeing their neurologists? I can tell you one thing that we know historically is that if you go in and you ask the neurologist: “What percentage of your patients, if I go through all your records that are sitting right there behind your nurse, are on one of the MS treatments?” And they’ll say: “80%, 90%.” They’ll say something very high. But if you actually pull records, it’s lower than that. And those are still people who may be coming, but less frequently. Some of those people have fallen out.
They are either just being handled by their primary care physician or they are only showing up at the neurologist when they are really having a significant clinical flare. So, how do we track them back in? Well, the first is, I’m not really too worried about, I mean right now we just have to deal with the pent-up demand of the patients that are right there in front of the neurologist. I think that the neurologists are then going to start to pull them back, but I’ll just give you a couple of other ways that the channels work.
One is the National MS Society and all the local chapters. Most MS patients that I have met are members of that or get information from that. So that’s a new information source for them even if they are not going through their neurologist.
The second is that there has actually been a lot of press activity in the last 60 days on MS. So you see a lot of people in the lay press, you know, ABC, NBC, you know, putting out stuff, getting people to ask questions: “Well, there’s something new, should I think about that again?” So, I think there are a couple of other channels out there independent of what we’re doing that are drawing people in. And the third thing I would say is, I don’t know if you’ve seen – where do you live, down here?

Q. In Connecticut.

Jim Mullen: Ok, in Connecticut. So my mother calls me up – this is your standard mother survey, right? – so my mother calls me up and she goes: “Are you hearing this radio advertisement, St. Elizabeth’s Hospital, you know, in Boston?” And they’re sitting there with radio advertisement trying to pull people in to put them on Tysabri.
That has nothing to do with us. I was surprised to hear it, and then I start to see little squibs. There’s a whole bunch of activity now going on with these MS practices, trying to get the awareness up and bring people back into the neurologist’s office. Yes, so, it may take us a little longer to get there, in terms of bringing those folks in. But they’re out there. And there are ways to get at them and in the first place is, a lot of them are still sitting in the neurologists’ practices. They are not coming in for semi-annual visits. They are only coming in when they have a flare.

Q. A question on manufacturing. You just talked about the capacity as being as much as 40,000 patients by the end of this year. Just by some chance, if sales of Tysabri are that strong, how would you think about managing the potential capacity constraints that you would run into?

Jim Mullen: Yeah, um, I went into a fair bit of gory detail on the earnings call on the manufacturing capacity. But it’s really a moving target. And the moving parts are step-wise additions to the license in the current license facility, licensing of the bulk facility at Oceanside, and then improvements to the manufacturing process. So, our capacity, when I gave you the snapshot of 40,000, I said, you know, if we’ve got a projectory going past 40,000, this year ..
So, then starting it at whatever 0 was on November 30th [2004], 40,000 on December 31st, you know, that will start to put some pressure on the supply chain. But, in fact, our capacity is stepping up all through the year. And so, when I talk about capacity, I’m not worried about getting them the first shipment; I’m worried about getting them the 12th shipment. So that, once we’ve got somebody on product, we cannot interrupt the supply chain. So we are always looking well ahead.
So when I talk about 40 [thousand], well that’s kind of the ramp rate we think we can handle in the supply chain this year. But in fact, our supply chain capacity is going to be a lot higher than that by the end of the year. It’s really .. there’s two factors to deal with here. One is just bulk capacity, and of course, what inventory we have sitting behind there. And we’re making more than we need at this point.
So, you know, we’re stockpiling inventory. And the second is just scheduling the fills, because the fills – it’s not a capacity problem, it’s a just a scheduling issue, because you’ve got to schedule it. You’ve got to get the product released. And that’s a fairly long cycle and all that. Ok? Now 40,000 patients would be well north of any launch in this space by a wide mark.

Q. But, to be fair, you did say that there are 100,000 people that are off therapy, granted you’ve got to find those patients. And you also did say that, what is it, 150,000 that are unhappy with their current therapies, so I mean, theoretically, it could happen.

Jim Mullen: Well, it could happen. But there is some natural speed limit of how many you can push through the system in the neurologist’s office. So, you know, I think you have to factor that in to. I mean, obviously, they can handle the 15,000–20,000 newly diagnosed in the U.S. each year without a big problem. But then go try to layer on that 5x that or 2x that of new diagnoses, new product switches that require more handling, so there is a speed limit in the process.

Q. How much of the manufacturing, getting from 40,000 to 70,000 patients in North Carolina, which I think is the max capacity, how much of that requires FDA approval versus just, you know, you fine-tuning the process on your own without regulatory o.k.s?

Jim Mullen: So what I said – and this is true for all 3 of the plants – the configuration are: there are 3 trains. Each train has two bioreactors that are 15,000 liters. And there’s two purifications suites. The initial approval is for one of the trains and one of the purification suites.
All the trains are identical. But you only get, with the FDA, you get approval only for product that you have made in the equipment and validated the process and the equipment. So then you have to go and make material, get it validated, submit the data. Those will be CB30s. And so we will submit the next train this quarter, and the next train after that.
So the whole RTP facility will fairly shortly be completely licensed. That’s one part. And then the Oceanside facility, brand new facility, so that would be the first part it ever got licensed on. We would file for licensure by the end of this year. If it is just a standard approval process, that means it would be somewhere in 2006 that we would have approval for that facility.
Then you have to layer in there process improvements. And we’ve got improvements to the current process which we would anticipate would be minor changes again in a CB30. That would step up the capacity, you know, 25% or so. And then we’ve got a much higher producing process that is at least 2x of the current process.
And that has been run at large scale. We’ve got to do the validations on some of the PKPD [?] work for the FDA and file that process. So that will take somewhat longer.

Q. Some of your target markets for Tysabri are the off-treatment patients or “quitters.” Have you profiled this group much? I mean, how well do we know these patients? Is there a risk that they are a group of refractory patients or chronically non-compliant? Or are there economic issues why they are not on MS drugs?

Jim Mullen: Yep. Well, I think we have profiled them fairly well. Keep in mind on the current therapy: on Avonex we see about 1 ½ per cent per month of the patients are dropping off therapy for a variety of reasons. Some of them are switching, some are just dropping off therapy.
The other products are a little higher than that, at least in our estimation. So, there’s a fair bit of churn in that marketplace. So some amount of patients – we actually know who they are because they are sitting in the database – they were once customers. I think we have a reasonable profile on them. I would say that it’s the usual rule: there’s a chunk of them that are fairly easy to get at, but that last percentage is going to be more difficult.
Now in terms of the reimbursement, we do have Medicare coverage on Avonex and we already have the C-code in Medicare, already. So, it’s supposed to take 6 months and they did it in a month. I don’t really think there is going to be big economic issues.
As a benchmark to that, on Avonex, because we do have a underinsured or uninsured program for folks. That maybe represents 5% or 6% or 7% of the total population are on product at some kind of a discount supported by us. I don’t know a reason why it would necessarily be different for Tysabri.

Q. Can you just review the pricing in the MS marketplace? What is the annual cost of therapy for Tysabri, Avonex, Rebif, Copaxone?

Jim Mullen: I can review it, but, you, I think it would be easier for me to send it to you, because I may not get the numbers exactly right. But I think the Tysabri, if you take the full 13 doses, is $23,200. Rebif, high dose: $17,000, mid-17,000 somewhere, just over 17. Copaxone, Betaseron and Avonex are all right around 14.
Is that right, Elizabeth? Ok. There’re all a little bit different, but there are basically right in that range. They are all right around 14 and a few hundred dollars.

Q. On the quitters, and you said you had a database of patients who have quit therapy, what percentage of the patients who are “quitters” would you say stopped therapy because of the side effects, because they just couldn’t take the nausea, the issues that the other drugs have?

Jim Mullen: I think it is fairly high. I think people get very tired of .. On the interferons, they typically, the typical patient will tolerize to the flu-like symptoms in about 6 months, sometimes less. So that becomes less of an issue. And you have actually the patients who are being successful who will actually report sort a pickup of energy, and things like that.
But there’s still that group that, you know, are getting the flu-like symptoms. And they are just tired of it. And we know that our patients when they start on Avonex — and this is one of the powers of our customer service model – about six months in, they begin to have the question, either they are frustrated with the flu-like symptoms or they are beginning to have the question if this is working at all?
And they have sort of a similar crisis about one year in. And if you’re coming through those, as long as you’re seeing efficacy, they stay on. But there’s a fair frustration rate with the patients in MS.
And I think the one thing that we are starting to hear back from some of the round tables with doctors is, that they underestimated how frustrated the patients are with that side effect, and how much, therefore, there may be pressure to just change products even if they are stable on the product.
And that is a segment of the market we haven’t talked about. We said, we’re not recommending to people, but they are starting to get, at least, questions from patients: “Gees, doc, I hate taking these drugs, should I consider switching?” So, I think it is a big factor.

Q. On pricing, how much have you raised price in the last two years, and how much pricing flexibility do you think you have going forward?

Jim Mullen: Elizabeth, do you know the precise number on the pricing the last few years? It’s in the 20% range, is my recollection.

Q. Over the two years?

Jim Mullen: Yeah. I don’t think there is going to be tons of pricing flexibility as you move into this ASP+6 model starting in 2006. There is a certain dynamic in there that is going to sort of create a downward pressure on how much you can raise your price at any one time. Because .. probably more true in something like oncology, where you never want to put your physicians under water.
If it’s a pharmacy benefit, it’s a little bit a different issue, but you have always got the comparator that all the payers are looking at: “What is the Medicare price? What’s the Federal price? What’s our price?” So I think it gets less flexibility in the future.

Question: You’re talking about Avonex.

Jim Mullen: I’m talking about all products.

Q. But on the Avonex front, I would think that you might have more pressure.

Jim Mullen: Well, we might have more pricing flexibility in that we are the lowest price product right now or tied with the lowest price product in that space.

Q. Can you just review the pricing in the MS marketplace? What is the annual cost of therapy for Tysabri, Avonex, Rebif, Copaxone?

Jim Mullen: I can review it, but, you, I think it would be easier for me to send it to you, because I may not get the numbers exactly right. But I think the Tysabri, if you take the full 13 doses, is $23,200. Rebif, high dose: $17,000, mid-17,000 somewhere, just over 17. Copaxone, Betaseron and Avonex are all right around 14. Is that right, Elizabeth? Ok. There’re all a little bit different, but there are basically right in that range. They are all right around 14 and a few hundred dollars.

I wish Biogen would stop quoting the wholesale cost of Tysabri as the annual cost of therapy. We have heard from potential users that the "real cost" per year is between $ 30,000 and $ 40,000, depending on what facility is used and how much profit that facility decides to make.

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